tbuckley/cabot-search huggingface dataset:
Detection of <i>BRCA1</i>, <i>BRCA2</i>, and <i>ATM</i> Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound
Authors: Kim N. Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J. Carl Barrett, Carrie A. Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R. Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, Elizabeth A. Harrington
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study. Patients and Methods: Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx. Results: 81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor. Conclusions: We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses.
Asialoglycoprotein Receptor 1 Functions as a Tumor Suppressor in Liver Cancer via Inhibition of STAT3
Authors: Xingxin Zhu, Guangyuan Song, Shiyu Zhang, Jun Chen, Xiaoyi Hu, Hai Zhu, Xing Jia, Zequn Li, Wenfeng Song, Jian Chen, Cheng Jin, Mengqiao Zhou, Yongchao Zhao, Haiyang Xie, Shusen Zheng, Penghong Song
Journal: Cancer Research (2022)

Abstract Liver cancer is characterized by aggressive growth and high mortality. Asialoglycoprotein receptor 1 (ASGR1), which is expressed almost exclusively in liver cells, is reduced in liver cancer. However, the specific mechanism of ASGR1 function in liver cancer has not been fully elucidated. On the basis of database screening, we identified ASGR1 as a tumor suppressor regulated by DNA methylation. Expression of ASGR1 was downregulated in liver cancer and correlated with tumor size, grade, and survival. Functional gain and loss experiments showed that ASGR1 suppresses the progression of liver cancer in vivo and in vitro. RNA sequencing and mass spectrometry showed that ASGR1 inhibits tyrosine phosphorylation of STAT3 by interacting with Nemo-like kinase (NLK). NLK bound the SH2 domain of STAT3 in an ATP-dependent manner and competed with glycoprotein 130 (GP130), ultimately suppressing GP130/JAK1-mediated phosphorylation of STAT3. ASGR1 altered the binding strength of NLK and STAT3 by interacting with GP130. Furthermore, the domain region of NLK was crucial for binding STAT3 and curbing its phosphorylation. Collectively, these results confirm that ASGR1 suppresses the progression of liver cancer by promoting the binding of NLK to STAT3 and inhibiting STAT3 phosphorylation, suggesting that approaches to activate the ASGR1–NLK axis may be a potential therapeutic strategy in this disease. Significance: ASGR1 downregulation by DNA methylation facilitates liver tumorigenesis by increasing STAT3 phosphorylation.
Rapamycin-encapsulated costimulatory ICOS/CD40L-bispecific nanoparticles restrict pathogenic helper T-B-cell interactions while in situ suppressing mTOR for lupus treatment
Authors: Jiali Zhang, Qianqian Guo, Dai Dai, Jian Yu, Liting Wang, Zhihua Wu, Huihua Ding, Nan Shen, Yourong Duan
Journal: Biomaterials (2022)
Commensal gut microbiota-based strategies for oral delivery of therapeutic proteins
Authors: Connie W. Woo, Patrick Tso, Jensen H.C. Yiu
Journal: Trends in Pharmacological Sciences (2022)

Therapeutic proteins are rarely available in oral dosage form because the hostile environment of the human gastrointestinal (GI) tract and their large size make this delivery method difficult. Commensal bacteria in the gut face the same situation; however, they not only survive but low levels of their structural components such as lipopolysaccharide (LPS), peptidoglycan, and flagellin are also consistently detectable in the circulatory systems of healthy individuals. This opinion article discusses how gut bacteria survive in the gut, how their components penetrate the body from the perspective of the bacteria's and the host's proactivity, and how orally administered therapeutic proteins may be developed that exploit similar mechanisms to enter the body.
AIDS Policy
Authors: David E. Rogers
Journal: JAMA (1993)

THE NATIONAL Commission on AIDS (the acquired immunodeficiency syndrome) was created by federal statute in 1989. Its major legislative mandate was to provide ongoing oversight of the nation's involvement in the human immunodeficiency virus (HIV) epidemic and to report on the response to the President, the Congress, and the American people. The Commission recently released its final report,<sup>1</sup>and we have issued public statements when particular AIDS policy issues have taken on national importance. The time to speak out has come again. Recently, two issues have arisen that once more threaten to divide us as we move into the 13th year of the HIV epidemic. They are deceptively simple: Should HIV prevention programs be narrowly targeted toward certain "at risk" groups, or should prevention programs focus more broadly on the universality of risk among all people? Since drug use is now linked to more than one third of all
Novel antitumor therapeutic strategy using CD4+ T cell-derived extracellular vesicles
Authors: Sanghee Shin, Inseong Jung, Dokyung Jung, Christine Seulki Kim, Sung-Min Kang, Suyeon Ryu, Sung-Jin Choi, Soojeong Noh, Jongwon Jeong, Beom Yong Lee, Jun-Kook Park, Jiwon Shin, Hanchae Cho, Jong-Ik Heo, Youngtae Jeong, Sun Ha Choi, Shin Yup Lee, Moon-Chang Baek, Kyungmoo Yea
Journal: Biomaterials (2022)
Remdesivir reduced upper respiratory tract SARS-CoV-2 viral RNA concentration in COVID-19 patients who developed pneumonitis
Authors: Christopher KC Lai, Grace CY Lui, Yuchen Wei, Ka Chun Chong, Zigui Chen, Lowell Ling, Rita WY Ng, Siaw SS Boon, Wendy CS Ho, Apple CM Yeung, David SC Hui, Paul KS Chan
Journal: Journal of Infection (2022)
Functional Asplenia in Hemoglobin SE Disease
Authors: BARRY L. ENGELSTAD
Journal: Clinical Nuclear Medicine (1982)

A patient with hemoglobin SE disease developed pneumonia complicated by splenic sequestration crisis and transient functional asplenia. These manifestations of hemoglobin SE disease have not been previously reported. Hemoglobin E, anemias associated with functional asplenia, and implications of the present case are discussed.
Sacubitril/valsartan versus ramipril for patients with acute myocardial infarction: win‐ratio analysis of the PARADISE‐MI trial
Authors: Otavio Berwanger, Marc Pfeffer, Brian Claggett, Karola S. Jering, Aldo P. Maggioni, Philippe Gabriel Steg, Roxana Mehran, Eldrin F. Lewis, Yinong Zhou, Peter van der Meer, Carmine De Pasquale, Béla Merkely, Gerasimos Filippatos, John J.V. McMurray, Christopher B. Granger, Scott D. Solomon, Eugene Braunwald
Journal: European Journal of Heart Failure (2022)
Primary surgery versus primary rehabilitation for treating anterior cruciate ligament injuries: a living systematic review and meta-analysis
Authors: Tobias Saueressig, Tobias Braun, Nora Steglich, Frank Diemer, Jochen Zebisch, Maximilian Herbst, Wolfgang Zinser, Patrick J Owen, Daniel L Belavy
Journal: British Journal of Sports Medicine (2022)

Objective Compare the effectiveness of primarily surgical versus primarily rehabilitative management for anterior cruciate ligament (ACL) rupture. Design Living systematic review and meta-analysis. Data sources Six databases, six trial registries and prior systematic reviews. Forward and backward citation tracking was employed. Eligibility criteria Randomised controlled trials that compared primary reconstructive surgery and primary rehabilitative treatment with or without optional reconstructive surgery. Data synthesis Bayesian random effects meta-analysis with empirical priors for the OR and standardised mean difference and 95% credible intervals (CrI), Cochrane RoB2, and the Grading of Recommendations Assessment, Development and Evaluation approach to judge the certainty of evidence. Results Of 9514 records, 9 reports of three studies (320 participants in total) were included. No clinically important differences were observed at any follow-up for self-reported knee function (low to very low certainty of evidence). For radiological knee osteoarthritis, we found no effect at very low certainty of evidence in the long term (OR (95% CrI): 1.45 (0.30 to 5.17), two studies). Meniscal damage showed no effect at low certainty of evidence (OR: 0.85 (95% CI 0.45 to 1.62); one study) in the long term. No differences were observed between treatments for any other secondary outcome. Three ongoing randomised controlled trials were identified. Conclusions There is low to very low certainty of evidence that primary rehabilitation with optional surgical reconstruction results in similar outcome measures as early surgical reconstruction for ACL rupture. The findings challenge a historical paradigm that anatomic instability should be addressed with primary surgical stabilisation to provide optimal outcomes. PROSPERO registration number CRD42021256537.
Measuring Medication Use, Obstacles, and Knowledge in Individuals With Cirrhosis
Authors: Archita P. Desai, Shahd Duzdar, Timothy Stump, Eric S. Orman, Lauren Nephew, Kavish R. Patidar, Marwan S. Ghabril, Geoffrey Block, Michael Fallon, Naga Chalasani, Patrick O. Monahan
Journal: Clinical Gastroenterology and Hepatology (2022)
Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease
Authors: Remi Mahmoud, Edo H.J. Savelkoul, Wout Mares, Rogier Goetgebuer, Ben J.M. Witteman, Daan B. de Koning, Sebastiaan A.C. van Tuyl, Itta Minderhoud, Maurice W.M. D. Lutgens, Dilek Akol-Simsek, Fiona D.M. van Schaik, Herma H. Fidder, Jeroen M. Jansen, Petra G.A. van Boeckel, Nofel Mahmmod, Carmen S. Horjus-Talabur Horje, Tessa E.H. Römkens, Jean-Frédéric Colombel, Frank Hoentjen, Bindia Jharap, Bas Oldenburg
Journal: Clinical Gastroenterology and Hepatology (2022)

Discontinuation of anti-tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing.This was a multicenter, prospective study in adult patients with Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3-4) versus complete (Mayo 0/SES-CD 0-2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use.Among 81 patients (CD: n = 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6-2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43-7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01-0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months.The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse.
Balancing activation and co-stimulation of CAR tunes signaling dynamics and enhances therapeutic potency
Authors: Yanting Duan, Jiangqing Chen, Xianhui Meng, Longwei Liu, Kai Shang, Xiaoyan Wu, Yajie Wang, Zihan Huang, Houyu Liu, Yanjie Huang, Chun Zhou, Xiaofei Gao, Yingxiao Wang, Jie Sun
Journal: Molecular Therapy (2022)

CD19-targeting chimeric antigen receptors (CARs) with CD28 and CD3ζ signaling domains have been approved by the US FDA for treating B cell malignancies. Mutation of immunoreceptor tyrosine-based activation motifs (ITAMs) in CD3ζ generated a single-ITAM containing 1XX CAR, which displayed superior antitumor activity in a leukemia mouse model. Here, we investigated whether the 1XX design could enhance therapeutic potency against solid tumors. We constructed both CD19- and AXL-specific 1XX CARs and compared their in vitro and in vivo functions with their wild-type (WT) counterparts. 1XX CARs showed better antitumor efficacy in both pancreatic and melanoma mouse models. Detailed analysis revealed that 1XX CAR-T cells persisted longer in vivo and had a higher percentage of central memory cells. With fluorescence resonance energy transfer (FRET)-based biosensors, we found that decreased ITAM numbers in 1XX resulted in similar 70-kDa zeta chain-associated protein (ZAP70) activation, while 1XX induced higher Ca
FOXP3 expression diversifies the metabolic capacity and enhances the efficacy of CD8 T cells in adoptive immunotherapy of melanoma
Authors: Enrique Conde, Noelia Casares, Uxua Mancheño, Edurne Elizalde, Enric Vercher, Roberto Capozzi, Eva Santamaria, Juan R. Rodriguez-Madoz, Felipe Prosper, Juan J. Lasarte, Teresa Lozano, Sandra Hervas-Stubbs
Journal: Molecular Therapy (2022)

Regulatory T cells overwhelm conventional T cells in the tumor microenvironment (TME) thanks to a FOXP3-driven metabolic program that allows them to engage different metabolic pathways. Using a melanoma model of adoptive T cell therapy (ACT), we show that FOXP3 overexpression in mature CD8 T cells improved their antitumor efficacy, favoring their tumor recruitment, proliferation, and cytotoxicity. FOXP3-overexpressing (Foxp3UP) CD8 T cells exhibited features of tissue-resident memory-like and effector T cells, but not suppressor activity. Transcriptomic analysis of tumor-infiltrating Foxp3UP CD8 T cells showed positive enrichment in a wide variety of metabolic pathways, such as glycolysis, fatty acid (FA) metabolism, and oxidative phosphorylation (OXPHOS). Intratumoral Foxp3UP CD8 T cells exhibited an enhanced capacity for glucose and FA uptake as well as accumulation of intracellular lipids. Interestingly, Foxp3UP CD8 T cells compensated for the loss of mitochondrial respiration-driven ATP production by activating aerobic glycolysis. Moreover, in limiting nutrient conditions these cells engaged FA oxidation to drive OXPHOS for their energy demands. Importantly, their ability to couple glycolysis and OXPHOS allowed them to sustain proliferation under glucose restriction. Our findings demonstrate a hitherto unknown role for FOXP3 in the adaptation of CD8 T cells to TME that may enhance their efficacy in ACT.
Clinical trial design in the era of precision medicine
Authors: Elena Fountzilas, Apostolia M. Tsimberidou, Henry Hiep Vo, Razelle Kurzrock
Journal: Genome Medicine (2022)

Abstract Recent rapid biotechnological breakthroughs have led to the identification of complex and unique molecular features that drive malignancies. Precision medicine has exploited next-generation sequencing and matched targeted therapy/immunotherapy deployment to successfully transform the outlook for several fatal cancers. Tumor and liquid biopsy genomic profiling and transcriptomic, immunomic, and proteomic interrogation can now all be leveraged to optimize therapy. Multiple new trial designs, including basket and umbrella trials, master platform trials, and N-of-1 patient-centric studies, are beginning to supplant standard phase I, II, and III protocols, allowing for accelerated drug evaluation and approval and molecular-based individualized treatment. Furthermore, real-world data, as well as exploitation of digital apps and structured observational registries, and the utilization of machine learning and/or artificial intelligence, may further accelerate knowledge acquisition. Overall, clinical trials have evolved, shifting from tumor type-centered to gene-directed and histology-agnostic trials, with innovative adaptive designs and personalized combination treatment strategies tailored to individual biomarker profiles. Some, but not all, novel trials now demonstrate that matched therapy correlates with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To further improve the precision medicine paradigm, the strategy of matching drugs to patients based on molecular features should be implemented earlier in the disease course, and cancers should have comprehensive multi-omic (genomics, transcriptomics, proteomics, immunomic) tumor profiling. To overcome cancer complexity, moving from drug-centric to patient-centric individualized combination therapy is critical. This review focuses on the design, advantages, limitations, and challenges of a spectrum of clinical trial designs in the era of precision oncology.
Prothrombin Levels Maintained With Meprobamate and Warfarin
Authors: Lawrence Gould
Journal: JAMA (1972)

Although meprobamate has been cited as one of several drugs having a potential for increasing coumarin metabolism through microsomal enzyme stimulation, the clinical effects of coadministration have not been well documented. A double-blind, randomized, seven-week study was carried out to compare the effects on prothrombin time of the administration or withdrawal of a maximal dose of meprobamate (2,400 mg/day) or placebo in 21 hospital outpatients (17 analyzed) who were stabilized with long-term anticoagulant (warfarin sodium) therapy. The addition of meprobamate showed some tendency toward reducing prothrombin time as compared with the addition of placebo. Statistically, this difference reached borderline significance (<i>P</i>=.10) at two weeks and significance (<i>P</i>=.03) at four weeks. Clinically, however, the difference was not significant, a fact supported by the failure of the meprobamate group to develop any greater change after discontinuation of medication than the placebo group.
Long-term Follow-up of Detaenial Sigmoid Neobladder Reconstruction for Paediatric Patients with Bladder and Prostate Rhabdomyosarcoma: Technique and Results from a Single High-volume Centre
Authors: Peng Xu, Chunxiao Chen, Binshen Chen, Enguang Bi, Wei Du, Ning Jiang, Zhe Liu, Hekui Lan, Manming Cao, Yazhen Liu, Jingwen Huang, Haiyan Shen, Cunrong Liu, Chunxiao Liu, Abai Xu
Journal: European Urology (2022)

Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma. Approximately 15-20% of RMS cases arise from the bladder and prostate (B/P). The optimal treatment strategy for B/P RMS remains unclear.To retrospectively evaluate the applicability of our procedure performed to treat paediatric patients with B/P RMS.This is a retrospective analysis from a single tertiary referral hospital. From August 2003 to March 2021, 62 children pathologically diagnosed with B/P RMS underwent radical cystectomy and orthotopic detaenial sigmoid neobladder reconstruction in our centre.Surgical procedures included laparoscopic radical cystectomy and detaenial sigmoid neobladder reconstruction, which is demonstrated in the accompanying video.Demographic, clinical, and follow-up data were collected. Perioperative and long-term oncological and functional outcomes were reported. A logistic regression analysis was also performed.All surgeries, including three intracorporeal laparoscopic surgeries, were completed successfully. Of the 62 patients, 54 were alive without evidence of disease recurrence or metastasis at the last follow-up. Five of the 14 >12-yr-old boys reported that they experienced erections. Two female patients >12 yr old reported that they menstruated. However, this was a retrospective study conducted at a single centre with limited surgeon experience.Our results confirmed the safety and feasibility of primary orthotopic sigmoid neobladder reconstruction after radical cystectomy for paediatric patients with B/P RMS. Good outcomes in terms of oncological control and functional recovery were achieved. The high histocompatibility and tissue adaptability of children are inspiring.We describe our stepwise technique of radical cystectomy and detaenial sigmoid neobladder reconstruction for paediatric patients with bladder and prostate rhabdomyosarcoma. With this technique, we were able to achieve good functional recovery without compromising cancer control and significantly increasing complications.
Trends in Cigarette Smoking in the United States
Authors: John P. Pierce
Journal: JAMA (1989)

Data from National Health Interview Surveys from 1974 through 1985 are used to project cigarette smoking prevalence to the year 2000. Smoking prevalence in the United States has declined at a linear rate since 1974. If this trend continues, in the year 2000,22% of the adult population (40 million Americans) will be smokers. By the year 2000, the major inequalities in prevalence will occur among educational categories. At least 30% of those who have not proceeded beyond a'high school education will be smokers, whereas less than 10% of college graduates will smoke. Among the other sociodemographic subgroups, smoking prevalence is expected to decrease by the year 2000 to 20% among men, to 23% among women, to 25% among blacks, and to 21% among whites. Between 1974 and 1985, approximately 1.3 million persons per year became former smokers, indicating considerable success in public health efforts to encourage people to stop smoking. However, in the early 1980s, approximately 1 million new young persons per year were recruited to the ranks of regular smokers. This is equivalent to about 3000 new smokers each day. Public health efforts need to focus more on preventing young people from starting to smoke, and such prevention efforts should particularly target less educated socioeconomic groups. (<i>JAMA</i>1989;261:61-65)